The role of nigrostriatal and striatal cell subtype signaling in behavioral impairments related to schizophrenia

项目总结/摘要 在精神障碍中，过量的黑质纹状体（NS）多巴胺信号与幻觉、妄想和幻觉有关。 对抗精神病药物有反应的混乱的积极思维症状。相比之下， 这些疾病中的阴性和认知症状在很大程度上对治疗无反应。抗精神病药物 被认为是通过阻断D2多巴胺受体（D2 R），这是高度表达在纹状体工作。这 观察和增加全脑多巴胺（通过安非他明治疗）可以改善认知的事实 助长了过量多巴胺与认知和消极症状无关的教条。然而，在患者 在精神分裂症中，多巴胺在纹状体（而不是整个大脑）中选择性地增加。而且 纹状体还表达D1多巴胺受体（D1 R），其不是当前抗精神病药的靶向。 因此，多巴胺可能通过纹状体D1 R信号传导导致消极和认知症状，但这可能是一个潜在的原因。 这个想法从未经过直接测试。这项研究的目的是确定纹状体D1 R- 和D2 R表达的多刺投射神经元（SPN）差异性地导致多巴胺驱动的缺陷， 社会和认知功能。为了做到这一点，我开发了一种方法来模拟特定于通路的过量， 通过选择性表达SNc中的兴奋性阳离子通道TRPV 1观察精神分裂症中的多巴胺 Trpv 1基因敲除小鼠的多巴胺神经元。用TRPV 1激动剂辣椒素全身治疗这些小鼠 增加背侧纹状体的多巴胺释放，但不增加前额叶皮层（PFC）的多巴胺释放，如dLight所测 使用体内纤维光度法测定荧光。以这种方式选择性地驱动NS多巴胺传输增加 运动，但也扰乱社会互动和工作记忆，行为代理的负面和 认知症状在这里，我建议以下列具体目标来扩展这些发现： (1)在目标1中，我将使用基于TRPV 1的方法和微型显微镜来成像细胞中的Ca 2+活性。 D1-或D2-SPN在正常和高多巴胺能条件下，以确定如何改变活动，在每个SPN 类型导致社会和认知行为的缺陷。(2)在目标2中，我将使用基于TRPV 1的方法 通过对表达D1 R或D2 R的SPN进行化学遗传学操作，将其活性与特异性 选择性驱动纹状体多巴胺释放导致的行为改变。通过定义纹状体D1的作用， 和D2-SPNs在多巴胺驱动的与精神分裂症症状相关的行为结构变化中， 我的实验有可能为精神病找到新的治疗策略， 全面解决其症状。在这个奖学金下，我计划接受体内成像的培训， 电生理记录技术，编码和数据分析，赠款和手稿写作，教学和 导师，并进一步了解基底神经节相关的功能障碍和精神疾病。我的训练 目标，致力于推进科学研究和学术界的多样性，强大的导师团队，以及 在西北充满活力的学术环境确保我将达到成功的NRSA研究员。

Project Summary/Abstract In psychotic disorders, excess nigrostriatal (NS) dopamine signaling is linked to hallucinations, delusions, and disorganized thought—positive symptoms that respond to antipsychotic drugs. By contrast, the prevalent negative and cognitive symptoms in these disorders are largely unresponsive to treatment. Antipsychotic drugs are thought to work by blocking D2 dopamine receptors (D2Rs), which are highly expressed in the striatum. This observation and the fact that increasing brain-wide dopamine (via amphetamine treatment) improves cognition fueled the dogma that excess dopamine is not involved in cognitive and negative symptoms. However, in patients with schizophrenia, dopamine is selectively increased in the striatum (not throughout the brain). Moreover, the striatum also expresses D1 dopamine receptors (D1Rs), which are not targeted by current antipsychotics. Therefore, dopamine may contribute to negative and cognitive symptoms through striatal D1R signaling, but this idea has never been directly tested. The goal of the proposed research is to determine whether striatal D1R- and D2R-expressing spiny projection neurons (SPNs) differentially contribute to dopamine-driven deficits in social and cognitive function. To do this, I developed an approach to mimic the pathway-specific excess in dopamine observed in schizophrenia by selectively expressing the excitatory cation channel TRPV1 in SNc dopamine neurons of Trpv1 knockout mice. Systemically treating these mice with the TRPV1 agonist capsaicin increases dopamine release in the dorsal striatum but not prefrontal cortex (PFC) as measured by dLight fluorescence using in vivo fiber photometry. Selectively driving NS dopamine transmission in this way increases locomotion, but also disrupts social interaction and working memory, behavioral proxies for negative and cognitive symptoms. Here I propose to expand on these findings with the following specific aims: (1) In Aim 1, I will use the TRPV1-based approach with miniature microscopes to image Ca2+ activity in D1- or D2-SPNs under normal and hyperdopaminergic conditions to determine how altered activity in each SPN type contributes to deficits in social and cognitive behavior. (2) In Aim 2, I will use the TRPV1-based approach with chemogenetic manipulations of D1R- or D2R-expressing SPNs to causally link their activity to specific changes in behavior caused by selectively driving striatal dopamine release. By defining the roles of striatal D1- and D2-SPNs in dopamine-driven changes in behavioral constructs related to the symptoms of schizophrenia, my experiments have the potential to identify novel therapeutic strategies for psychosis that more comprehensively address its symptoms. Under this fellowship, I plan to receive training in in vivo imaging and electrophysiology recording techniques, coding and data analysis, grant and manuscript writing, teaching and mentorship, and further knowledge of basal ganglia-related dysfunction and psychiatric disease. My training goals, dedication to progressing science research and diversity in academia, strong mentorship team, and the vibrant academic environment at Northwestern ensure I will reach success as an NRSA fellow.